The compounds designated as lantibiotics are peptides belonging to the general definition of antibiotic compounds, characterized by the presence of the amino acids lanthionine and/or 3-methyllanthionine. The term lantibiotic thus defines a structural feature of these compounds and not necessarily a common possible pharmacological activity. In fact, some lantibiotics possess antibacterial activity while others are totally devoid of it. Among the lantibiotics possessing antibacterial activity, of particular relevance are those active against methicillin-resistant Staphylococcus aureus (MRSA), which can be of considerable interest in medicine. All the lantibiotics endowed with antibacterial activity described so far, exert their action by interfering with cell wall biosynthesis, through sequestration of a key intermediate in peptidoglycan formation.
The antibacterial lantibiotics can be broadly divided into two groups on the basis of their structures: type-A lantibiotics are typically elongated, amphiphilic peptides, while type-B lantibiotics are compact and globular. Nisin is the typical representative of type A lantibiotic, whereas actagardine and mersacidin belong to the type B lantibiotic subclass. Remarkably, despite differences in shape and primary structure, both nisin-type and mersacidin-type lantibiotics interact with the membrane-bound peptidoglycan precursor lipid II. Furthermore, while the spectrum of antibacterial activity is generally restricted to Gram-positive bacteria, individual members of subclasses A and B greatly vary in their potency. Overall, the structural elements responsible for increased target binding and/or enhanced antibacterial activity in lantibiotics are poorly understood.
Traditionally, lantibiotics have been isolated mostly from the order Firmicutes (low G-C Gram-positive bacteria) and relatively few have been described from the Actinomycetales, the order best known for the ability to produce a large variety of other antibacterial agents. Actagardine and the recently described 107891 (International Publication Number WO2005/014628) are representative lantibiotics produced by the Actinomycetales.
These lantibiotics are active in vitro against Methicillin-Resistant Staphylococcus aureus (MRSA), streptococci and enterococci. S. aureus can cause life-threatening infections and MRSA is of particular clinical significance because it is resistant to all penicillins and cephalosporins and also to multiple other antibiotics; in addition it easily spreads from patient to patient causing outbreaks of infection with important implications for healthcare facilities. Vancomycin resistant enterococci (VRE) are emerging as important hospital-acquired pathogens responsible for severe human infections (such as endocarditis, meningitis and septicemia) posing an increasing therapeutic challenge. Streptococcus pneumoniae and Moraxella catarrhalis are recognized important human pathogens. They are a common cause of respiratory tract infections, particularly otitis media in children and lower respiratory tract infections in the eldery. M. catarrhalis and S. pneumoniae have been recently accepted as the commonest pathogens of the respiratory tract.
Variants and/or derivatives of naturally occurring antibiotics have been long sought after and can be useful in medicine. They can be produced by chemical synthesis or by modification of a natural product, but most structural variations in naturally occurring antibiotics tend to abolish or severely impair their antibacterial activity. This is particularly true in the field of lantibiotics, where structure-activity relationships (SAR) are poorly defined, in the absence of molecular details about antibiotic-target interactions. Furthermore, other factors likely to contribute to antibacterial potency are the diffusion rate of the compound to the target, after crossing the thick peptidoglycan layer, and possible interactions with polar, charged and hydrophobic moieties present on the protective external surfaces of the bacterial cell. An additional element rendering unpredictable the outcome of lantibiotic modifications is the existence of unrelated compounds possessing a similar mechanism of action, preventing conclusions drawn from SAR studies on one subtype to be applied to the other.